The objective of our present study is to develop novel inhibitors for MMP-2 for acute cardioprotection. In a series of pilot studies, novel substituted carboxylic acid derivatives were synthesized based on imidazole and thiazole scaffolds and then tested in a screeening cascade for MMP inhibition. We found that the MMP-inhibiting effects of imidazole and thiazole carboxylic acid-based compounds are superior in efficacy in comparison to the conventional hydroxamic acid derivatives of the same molecules. Based on these results, a 568-membered focused library of imidazole and thiazole compounds was generated in silico and then the library members were docked to the 3D model of MMP-2 followed by an in vitro medium throughput screening (MTS) based on a fluorescent assay employing MMP-2 catalytic domain. Altogether 45 compounds showed a docking score of >70, from which 30 compounds were successfully synthesized. Based on the MMP-2 inhibitory tests using gelatin zymography, 7 compounds were then selected and tested in neonatal rat cardiac myocytes subjected to simulated I/R injury. Six compounds showed significant cardio-cytoprotecion and the most effective compound (MMPI-1154) significantly decreased infarct size when applied at 1 μM in an ex vivo model for acute myocardial infarction. This is the first demonstration that imidazole and thiazole carboxylic acid-based compounds are more efficacious MMP-2 inhibitor than their hydroxamic acid derivatives. MMPI-1154 is a promising novel cardio-cytoprotective imidazole-carboxylic acid MMP-2 inhibitor lead candidate for the treatment of acute myocardial infarction.

dc.relation.ispartof

urn:issn:1663-9812

dc.title

Development of Matrix Metalloproteinase-2 Inhibitors for Cardioprotection

dc.type

Journal Article

dc.date.updated

2018-06-05T07:29:01Z

dc.language.rfc3066

en

dc.identifier.mtmt

3360745

dc.identifier.wos

000429284100002

dc.identifier.pubmed

29674965

dc.contributor.department

SZTE/ÁOK/Biokémiai Intézet

dc.contributor.department

SE/AOK/I/Farmakológiai és Farmakoterápiás Intézet

dc.contributor.institution

Szegedi Tudományegyetem

dc.contributor.institution

Semmelweis Egyetem

dc.mtmt.swordnote

Bencsik P and Kupai K have contributed equally to this work.
Doman G and Ferdinandy P joint last authors.